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Using tramadol to monitor hepatic drug metabolism in the critically ill


Previously, we have demonstrated significant inhibition of hepatic drug metabolism by the enzymes cytochrome P450 (CYP) 3A4 and 3A5 in acute kidney injury (AKI) using midazolam as a probe drug [1, 2]. We are now developing the use of tramadol as a probe drug to test the hypothesis that CYP2D6 function is also inhibited by AKI in critical illness. In this study we sought to determine whether a single timepoint tramadol concentration could be identified as a reliable surrogate for measurement of a full area under the concentration time curve after intravenous administration in adults.


We conducted a study of 10 critically ill patients in our hospital's general critical care unit. Tramadol 10 mg was given intravenously, and serum was taken at 0.5, 1, 2, 3, 4 and 8 hours for determination of concentrations of tramadol ([tramadol]) and its two main metabolites. Inclusion criteria: age >18 years, predicted ICU stay >48 hours. Exclusion criteria: recent receipt of tramadol or major CYP2D6 inhibitors, hepatic failure, pregnancy/breastfeeding.


There was a strong correlation between the area under the curve (AUC) of the [tramadol]-time graph and t = 4 hours [tramadol], P < 0.0001, r = 0.983. See Figure 1. The [tramadol] at other timepoints correlated less strongly with the AUC. The mean [tramadol] at 4 hours was 29.7 ng/ml (24.3 to 35.1) and the mean AUC was 257 ng/hour/ml (211 to 303). Analysis of tramadol metabolites confirmed that CYP2D6 was predominantly responsible for tramadol metabolism.

Figure 1
figure 1

Correlation of [tramadol] at t = 4 hours and AUC [tramadol]-time graph. iv, intravenous.


A single blood sample, taken 4 hours post-intravenous tramadol injection, reliably predicts integral tramadol exposure in critically ill adults and may be useful for assessing CYP2D6 function.

A larger study of the influences of AKI and CYP genotype on hepatic drug metabolism in the critically ill is underway.


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Correspondence to K Lane.

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Lane, K., Dixon, J., McKeown, D. et al. Using tramadol to monitor hepatic drug metabolism in the critically ill. Crit Care 16, P343 (2012).

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  • Tramadol
  • Acute Kidney Injury
  • Critical Care Unit
  • Probe Drug
  • CYP2D6 Inhibitor